Superstolides A and B are marine natural products that were isolated from the deep-water marine sponge Neosiphonia supersets. These two molecules are highly cytotoxic against various human cancer cells including bronchopulmonary non-small cell lung carcinoma. However, due to the scarcity of these compounds, there has not been enough material for further biological investigation. The potent anticancer activity of Superstolides A and B coupled with their challenging molecular structure make these molecules attractive synthetic targets. However, a complete total synthesis has not yet been reported. The long-term goal of this research is to develop highly effective anticancer agents from Superstolides A and B, and to carry out the molecular design, chemical synthesis and biological testing of simpler biological mimics of these two molecules. The central hypothesis of this proposal is that the highly convergent and stereoselective total synthesis based on the new Diels-Alder reaction developed in our laboratory will provide a sufficient quantity of the target materials for extensive biological investigation, and will allow us to elucidate the molecular target(s) of this group of highly potent anticancer marine natural products. The specific aims of this proposal are: 1. To conduct model studies for the construction of the 16-membered macrolactone present in the target molecules, including: 1a. A new efficient synthesis of allyl sulfones employing Negishi coupling between a-sulfonyl zinc chloride and vinyl halide;1b. A convergent synthesis of the 16-membered macrolactone model compound;c. Preparation and biological testing of simplified biological mimics without cis-fused decalin. 2. To develop a highly convergent and stereocontrolled strategy for the total synthesis of the anticancer natural products Superstolides A and B, including: 2a. Further investigate novel asymmetric Diels-Alder reactions employing 1,3-dienes derived from chiral 4-t-butyldimethylsilyloxy-2-cyclohexenone;2b. Synthesis of the highly functionalized cis-decalin portion of Superstolides A and B employing a combination of our asymmetric Diels-Alder reaction and an anionic Oxy-Cope rearrangement;2c. Complete the total synthesis of Superstolides A and B. 3. To conduct a biological investigation of Superstolides A and identify its cellular target(s), including: 3a. Test the in vitro anticancer activity and selectivity of Superstolides A;3b. Synthesize biotinylated-Superstolides A as a molecular probe fortarget(s) identification;3c. Identification and verification of the drug target(s). In summary, the proposed research is innovative in its approach and has significance in the field of the development of new anticancer agents.